FEATURE Advances and developments in medical retina BY ROD MCNEIL The author provides an update on late breaking clinical trial results in neovascular age-related macular degeneration (nAMD) and presentations on diabetes management from the American Academy of Ophthalmology Retina Subspecialty Day, held during the Academy’s annual meeting in Chicago, October 2018. Late breaking developments and predictive of continuing on that same four- or two-week adjustment increments, clinical trial results in nAMD quarterly treatment interval until week minimum treatment interval of eight weeks Brolucizumab in nAMD: HAWK and 96. Of the patients on brolucizumab 6mg and a maximum extension of 16 weeks) for HARRIER 96-week results who successfully completed year one on treatment naive nAMD patients through In the HAWK and HARRIER phase 3 nAMD a q12w dosing interval (i.e., 56% in HAWK 96 weeks. Mean BCVA gains from baseline (~55 letters) were 8.4 to 9.0 letters at week studies, the primary endpoint of non- and 51% in HARRIER), 82% in HAWK and 52 and 6.1 to 7.6 letters at week 96 for inferiority of brolucizumab 6mg (Novartis) 75% in HARRIER were maintained on a the four-week and two-week adjustment to aflibercept (Eylea®, Regeneron, Bayer) in q12w dosing interval in year two (overall, groups, respectively [4-6]. There was a mean change in best corrected visual acuity ~46% in HAWK and 38% in HARRIER). The mean of 10.4 injections given overall, (BCVA) from baseline was met at week 48 overall safety profile of brolucizumab was with a mean of 3.6 to 3.7 injections in the [1]. The study design of both trials involved comparable to aflibercept. second year. At the week 52 study visit, a matched loading phase up to week 16, 57% of study patients had a next intended followed by a maintenance phase of fixed Use of aflibercept treat-and-extend in injection interval of ≥12 weeks based on brolucizumab dosing every 12 weeks with ALTAIR: 96-week outcomes the next scheduled treatment, and almost an option to adjust to fixed eight-weekly The updated EU label for aflibercept 60% of the overall study population had dosing based on masked disease activity permits treat-and-extend dosing beyond a last injection interval ≥12 weeks at final every eight weeks in the first year of assessment at defined visits (q12w/q8w) or study visit at week 96 [Figure 1]. Results treatment for nAMD, with flexibility to aflibercept given every eight weeks (q8w) demonstrate that extended dosing with extend or adjust by four- or two-week through 96 weeks. afliberept after an initial loading phase increments, based on evidence of efficacy The BCVA achieved by brolucizumab is effective in improving and maintaining at week 48, the primary endpoint, from the Japanese ALTAIR clinical trial [3]. vision through 96 weeks, with a reduced was maintained at week 96 [2]. Table 1 The ALTAIR study assessed the efficacy treatment burden in the second year and summarises topline results at 96 weeks and safety of aflibercept therapy using a majority extended to quarterly or longer [2]. Successful completion of q12w two different treat-and-extend regimens dosing intervals. brolucizumab dosing at week 48 was highly beyond every-eight-weeks (with either Safety and efficacy of abicipar in patients with nAMD SEQUOIA and CEDAR are two randomised, double-masked, parallel-group phase 3 clinical trials designed to evaluate the safety and efficacy of intravitreal abicipar pegol (Allergan) compared with ranibizumab (Lucentis®, Novartis) in treatment-naive patients with nAMD. Both abicipar q8w and q12w regimens (after three loading doses at weeks one, four and 12) met the prespecified criteria for non-inferiority to monthly ranibizumab for stable vision (loss of <15 letters from baseline) at week 52 in both trials, with more than 91% of abicipar patients achieving stable vision [7]. The q8w and q12w regimens in SEQUOIA and the q8w regimen in CEDAR met the prespecified Figure 1: ALTAIR 96-week results showing last injection interval at final study visit week 96 [5,6]. criteria for non-inferiority to ranibizumab Eye News | FEBRUARY/MARCH 2019 | VOL 25 NO 5 | www.eyenews.uk.com FEATURE Table 1: Topline 96-week results of HAWK AND HARRIER [2]. HAWK 96 WEEKS HARRIER 96 WEEKS Brolucizumab 6mg Aflibercept 2mg Brolucizumab 6mg Aflibercept 2mg q12w/q8w* q8w* q12w/q8w* q8w* n=360 n=360 n=370 n=369 Baseline VA and CST BCVA, mean (SD), ETDRS letters 60.8 (13.66) 60.0 (13.92) 61.5 (12.59) 60.8 (12.93) CST, mean (SD), µm 463.1 (166.62) 457.9 (146.37) 473.6 (171.39) 465.3 (151.21) Outcome measure: Mean change in BCVA, ETDRS +5.9 +5.3 +6.1 +6.6 letters Absolute reduction in CST, µm 175 149 198 155 Presence of retinal fluid, % 24 37 24 39 Presence of sub-RPE fluid, % 11 15 17 22 Patients with ≥15 letter loss, % 8.1 7.5 7.0 7.6 Abbreviations: BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; CST, central subfield thickness; RPE, retinal pigment epithelium. * Following matched treatment loading phase up to week 16. for the key secondary efficacy endpoint maintained through week 52, with both fixed 24-week PDS refills vs. monthly mean BCVA change from baseline at faricimab dosing regimens comparable ranibizumab injections, began enrolling in week 52. Reductions from baseline in to monthly ranibizumab (+11.42, +10.08 September 2018. central retinal thickness (CRT) at week 52 and +9.59 letters from mean VA at were similar between abicipar treatment baseline of 60.4, 57.8 and 55.3 letters Diabetes: lessons learned, new arms (six to eight injections) and the for faricimab q16w, faricimab q12w and treatment paradigms for diabetic ranibizumab treatment arm (13 injections) monthly ranibizumab groups, respectively). macular oedema and diabetic in both SEQUOIA and CEDAR. BCVA and Anatomic improvements were comparable retinopathy CRT improvements after the initial loading between faricimab treatment regimens and Anti-VEGF therapy is now the mainstay phase were maintained at week 52. monthly ranibizumab [8]. Treatment with of treatment of diabetic macular oedema Abicipar-treated patients had a higher faricimab was well tolerated with no new (DMO) and regarded as a viable alternative risk of developing intraocular inflammation safety signals identified. to panretinal photocoagulation (PRP) than ranibizumab-treated patients (overall, for proliferative diabetic retinopathy 15.3%-15.4% for abicipar-treated patients Port Delivery System implant with (PDR), explained Dr John A Wells III, West compared with 0.3% for the ranibizumab ranibizumab Columbia, SC, USA. In a review of landmark arm). Most abicipar-treated patients with Study results from the ongoing phase 2 Diabetic Retinopathy Clinical Research intraocular inflammation had events of LADDER study of the investigational Port Network (DRCR.net) studies that have mild to moderate severity and were treated Delivery System with ranibizumab (PDS, changed treatment practice for diabetic- with topical corticosteroid drops. Allergan Roche) for nAMD were presented [9]. In the related retinal disease, he underscored core expects results from the MAPLE trial using PDS ranibizumab 100mg/mL treatment lessons learned from DRCR.net Protocol its further optimised formulation in first half arm (n=59), 80% of patients (previously trials I, T, U and S (Table 2) [10-15]: 2019. responsive to anti-VEGF therapy) went ≥6 • Treatment of centre-involved DMO with months until the first refill (primary analysis some vision loss should be initiated Simultaneous inhibition of Ang-2 and VEGF performed when last patient completed with anti-VEGF therapy and focal / grid with faricimab in nAMD: STAIRWAY phase the month nine visit). Median time to first laser deferred for at least six months 2 results required refill was 15.0 months, and BCVA (Protocol I). Combined inhibition of angiopoietin-2 and anatomic outcomes between PDS • The treatment burden following initial (Ang-2) and vascular endothelial growth with ranibizumab 100mg/mL and monthly intensive treatment in DMO declines over factor (VEGF) can reduce vascular intravitreal ranibizumab were comparable, time (Protocols I and T). destabilisation and leakage, and shows with improved or maintained vision over • Aflibercept is more effective than potential for increased durability in nAMD. nine months (from mean BCVA at baseline ranibizumab or compounded Faricimab (Roche) is a bispecific antibody of ~70 letters, mean change of +4.3 letters bevacizumab in centre-involving DMO designed specifically for intravitreal use to in the PDS 100mg/mL arm and +3.3 letters eyes with starting VA 20/50 or worse simultaneously bind to and neutralise both in the monthly intravitreal ranibizumab (Protocol T). Ang-2 and VEGF-A with high potency and arm at month nine). Subjects in the PDS • Aflibercept, bevacizumab or ranibizumab specificity. 100mg/mL group (n=59) required a mean can be given in eyes with baseline VA The phase 2 STAIRWAY clinical trial 2.4 ranibizumab treatments over 16.4 20/32 to 20/40, recognising, however, evaluated 6mg faricimab dosed either months compared with 16.8 injections that bevacizumab reduces optical every 16 weeks or every 12 weeks compared in the monthly ranibizumab arm (n=41). coherence tomography (OCT) oedema to monthly ranibizumab in patients with Postoperative vitreous haemorrhage rate less effectively and is more likely to result nAMD. Results show 65% of faricimab- in the PDS arm was significantly reduced in persistent DMO, which may also lead treated patients had no disease activity after a modified surgical technique was to inferior vision outcomes in eyes with 12 weeks after the last loading dose, implemented in the course of the trial. The OCT thickness greater than 400 microns while gains in BCVA from baseline were phase 3 Archway clinical trial, comparing (Protocol T).